↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Träfflista för sökning "WFRF:(Larsson Erik 1975) "

Sökning: WFRF:(Larsson Erik 1975)

Resultat 1-50 av 160

Sortera/gruppera träfflistan

Sortering: Träffar per sida:

Numrering	Referens	Omslagsbild	Hitta
1.	Basu, Swaraj, et al. (författare) Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing 2020 Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:12 Tidskriftsartikel (refereegranskat)abstract Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy. Author summary Deletions in the mitochondrial genome cause a wide variety of rare disorders, but are also linked to more common conditions such as neurodegeneration, diabetes type 2, and the normal ageing process. There is also a growing awareness that mtDNA duplications, which are also relevant for human disease, may be more common than previously thought. Despite their clinical importance, our current knowledge about the abundance, characteristics and diversity of mtDNA deletions and duplications is fragmented, and based to large extent on a limited view provided by traditional low-throughput analyses. Here, we describe a bioinformatics method, MitoSAlt, that can accurately map and classify mtDNA deletions and duplications using high-throughput sequencing. Application of this methodology to mouse models of mitochondrial deficiencies revealed a large number of duplications, suggesting that these may previously have been underestimated.
2.	Elias, Erik, 1979, et al. (författare) Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine. 2021 Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1 Tidskriftsartikel (refereegranskat)abstract Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several tumors clustered together in a limited intestinal segment. SI-NET also shows an unusual absence of driver mutations explaining tumor initiation and metastatic spread. The evolutionary trajectories that underlie multifocal SI-NET lesions could provide insight into the underlying tumor biology, but this question remains unresolved. Here, we determine the complete genome sequences of 61 tumors and metastases from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within single patients. Intra-individual comparisons revealed a lack of shared somatic single-nucleotide variants among the sampled intestinal lesions, supporting an independent clonal origin. Furthermore, in three of the patients, two independent tumors had metastasized. We conclude that primary multifocal SI-NETs generally arise from clonally independent cells, suggesting a contribution from a cancer-priming local factor.
3.	Elliott, Kerryn, et al. (författare) Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers. 2018 Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:12 Tidskriftsartikel (refereegranskat)abstract Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.
4.	Fredriksson, Nils Johan, 1979-, et al. (författare) Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature 2017 Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:5 Tidskriftsartikel (refereegranskat)abstract Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as influence on gene expression has been more elusive. Here, we show that frequently recurring promoter mutations in melanoma occur almost exclusively at cytosines flanked by a distinct sequence signature, TTCCG, with TERT as a notable exception. In active, but not inactive, promoters, mutation frequencies for cytosines at the 5' end of this ETS-like motif were considerably higher than expected based on a UV trinucleotide mutational signature. Additional analyses solidify this pattern as an extended context-specific mutational signature that mediates an exceptional position-specific vulnerability to UV mutagenesis, arguing against positive selection. We further use ultra-sensitive amplicon sequencing to demonstrate that cell cultures exposed to UV light quickly develop subclonal mutations specifically in affected positions. Our findings have implications for the interpretation of somatic mutations in regulatory regions, and underscore the importance of genomic context and extended sequence patterns to accurately describe mutational signatures in cancer.
5.	Göteson, Andreas, 1991, et al. (författare) Alterations in the Serum Proteome Following Electroconvulsive Therapy for a Major Depressive Episode: A Longitudinal Multicenter Study 2023 Ingår i: Biological Psychiatry: Global Open Science. - : Elsevier BV. - 2667-1743. ; 3:4, s. 884-892 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but the biological changes induced by ECT remain poorly understood.METHODS: This study investigated alterations in blood serum proteins in 309 patients receiving ECT for a major depressive episode. We analyzed 201 proteins in samples collected at 3 time points (T): just before the first ECT treatment session (T0), within 30 minutes after the first ECT session (T1), and just before the sixth ECT session (T2).RESULTS: Using statistical models to account for repeated sampling, we identified 152 and 70 significantly (,5% false discovery rate) altered proteins at T1 and T2, respectively. The most pronounced alterations at T1 were tran-siently increased levels of prolactin, myoglobin, and kallikrein-6. However, most proteins had decreased levels at T1, with the largest effects observed for pro-epidermal growth factor, proto-oncogene tyrosine-protein kinase Src, tumor necrosis factor ligand superfamily member 14, sulfotransferase 1A1, early activation antigen CD69, and CD40 ligand. The change of several acutely altered proteins correlated with electric current and pulse frequency in a dose-response-like manner. Over a 5-session course of ECT, some acutely altered levels were sustained while others increased, e.g., serine protease 8 and chitinase-3-like protein 1. None of the studied protein biomarkers were associated with clinical response to ECT.CONCLUSIONS: We report experimental data on alterations in the circulating proteome triggered by ECT in a clinical setting. The findings implicate hormonal signaling, immune response, apoptotic processes, and more. None of the findings were associated with clinical response to ECT.
6.	Göteson, Andreas, 1991, et al. (författare) Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder 2021 Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26, s. 7446-53 Tidskriftsartikel (refereegranskat)abstract The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium's mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder.
7.	Hagberg, Carolina E, et al. (författare) Vascular endothelial growth factor B controls endothelial fatty acid uptake. 2010 Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 464:7290, s. 917-21 Tidskriftsartikel (refereegranskat)abstract The vascular endothelial growth factors (VEGFs) are major angiogenic regulators and are involved in several aspects of endothelial cell physiology. However, the detailed role of VEGF-B in blood vessel function has remained unclear. Here we show that VEGF-B has an unexpected role in endothelial targeting of lipids to peripheral tissues. Dietary lipids present in circulation have to be transported through the vascular endothelium to be metabolized by tissue cells, a mechanism that is poorly understood. Bioinformatic analysis showed that Vegfb was tightly co-expressed with nuclear-encoded mitochondrial genes across a large variety of physiological conditions in mice, pointing to a role for VEGF-B in metabolism. VEGF-B specifically controlled endothelial uptake of fatty acids via transcriptional regulation of vascular fatty acid transport proteins. As a consequence, Vegfb(-/-) mice showed less uptake and accumulation of lipids in muscle, heart and brown adipose tissue, and instead shunted lipids to white adipose tissue. This regulation was mediated by VEGF receptor 1 and neuropilin 1 expressed by the endothelium. The co-expression of VEGF-B and mitochondrial proteins introduces a novel regulatory mechanism, whereby endothelial lipid uptake and mitochondrial lipid use are tightly coordinated. The involvement of VEGF-B in lipid uptake may open up the possibility for novel strategies to modulate pathological lipid accumulation in diabetes, obesity and cardiovascular diseases.
8.	Jonasson, Emma, 1987, et al. (författare) Identification of breast cancer stem cell related genes using functional cellular assays combined with single-cell RNA sequencing in MDA-MB-231 cells 2019 Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 10 Tidskriftsartikel (refereegranskat)abstract Breast cancer tumors display different cellular phenotypes. A growing body of evidence points toward a population of cancer stem cells (CSCs) that is important for metastasis and treatment resistance, although the characteristics of these cells are incomplete. We used mammosphere formation assay and label-retention assay as functional cellular approaches to enrich for cells with different degree of CSC properties in the breast cancer cell line MDA-MB-231 and performed single-cell RNA sequencing. We clustered the cells based on their gene expression profiles and identified three subpopulations, including a CSC-like population. The cell clustering into these subpopulations overlapped with the cellular enrichment approach applied. To molecularly define these groups, we identified genes differentially expressed between the three subpopulations which could be matched to enriched gene sets. We also investigated the transition process from CSC-like cells into more differentiated cell states. In the CSC population we found 14 significantly upregulated genes. Some of these potential breast CSC markers are associated to reported stem cell properties and clinical survival data, but further experimental validation is needed to confirm their cellular functions. Detailed characterization of CSCs improve our understanding of mechanisms for tumor progression and contribute to the identification of new treatment targets. © 2019 Jonasson, Ghannoum, Persson, Karlsson, Kroneis, Larsson, Landberg and Ståhlberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
9.	Karlsson, Joakim, et al. (författare) Transcriptomic Characterization of the Human Cell Cycle in Individual Unsynchronized Cells. 2017 Ingår i: Journal of molecular biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 429:24, s. 3909-3924 Tidskriftsartikel (refereegranskat)abstract The highly fine-tuned dynamics of cell cycle gene expression have been intensely studied for several decades. However, some previous observations may be difficult to fully decouple from artifacts induced by traditional cell synchronization procedures. In addition, bulk cell measurements may have disguised intricate details. Here, we address this by sorting and transcriptomic sequencing of single cells progressing through the cell cycle without prior synchronization. Genes and pathways with known cell cycle roles are confirmed, associated regulatory sequence motifs are determined, and we also establish ties between other biological processes and the unsynchronized cell cycle. Importantly, we find the G1 phase to be surprisingly heterogeneous, with transcriptionally distinct early and late time points. We additionally note that mRNAs accumulate to reach maximum total levels at mitosis and find that stable transcripts show reduced cell-to-cell variability, consistent with the transcriptional burst model of gene expression. Our study provides the first detailed transcriptional profiling of an unsynchronized human cell cycle.
10.	Landberg, Göran, 1963, et al. (författare) Characterization of cell-free breast cancer patient-derived scaffolds using liquid chromatography-mass spectrometry/mass spectrometry data and RNA sequencing data 2020 Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 31 Tidskriftsartikel (refereegranskat)abstract Patient-derived scaffolds (PDSs) generated from primary breast cancer tumors can be used to model the tumor microenvironment in vitro . Patient-derived scaffolds are generated by repeated detergent washing, removing all cells. Here, we analyzed the protein composition of 15 decellularized PDSs using liquid chromatography-mass spectrometry/mass spectrometry. One hundred forty-three proteins were detected and their relative abundance was calculated using a reference sample generated from all PDSs. We performed heatmap analysis of all the detected proteins to display their expression patterns across different PDSs together with pathway enrichment analysis to reveal which processes that were connected to PDS protein composition. This protein dataset together with clinical information is useful to investigators studying the microenvironment of breast cancers. Further, after repopulating PDSs with either MCF7 or MDA-MB-231 cells, we quantified their gene expression profiles using RNA sequencing. These data were also compared to cells cultured in conventional 2D conditions, as well as to cells cultured as xenografts in immune-deficient mice. We investigated the overlap of genes regulated between these different culture conditions and performed pathway enrichment analysis of genes regulated by both PDS and xenograft cultures compared to 2D in both cell lines to describe common processes associated with both culture conditions. Apart from our described analyses of these systems, these data are useful when comparing different experimental model systems. Downstream data analyses and interpretations can be found in the research article "Patient-derived scaffolds uncover breast cancer promoting properties of the microenvironment" [1] . (C) 2020 The Authors. Published by Elsevier Inc.
11.	Ligthart, S., et al. (författare) Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders 2018 Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 103:5, s. 691-706 Tidskriftsartikel (refereegranskat)
12.	Lind, Lars, et al. (författare) Longitudinal effects of aging on plasma proteins levels in older adults : associations with kidney function and hemoglobin levels 2019 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:2 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: A targeted proteomics chip has been shown to be useful to discover novel associations of proteins with cardiovascular disease. We investigated how these proteins change with aging, and whether this change is related to a decline in kidney function, or to a change in hemoglobin levels.MATERIAL AND METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, including 1,016 participants from the general population aged 70 at baseline, 84 proteins were measured at ages 70, 75, 80. At these occasions, glomerular filtration rate (eGFR) was estimated and the hemoglobin levels were measured.RESULTS: Sixty-one of the 84 evaluated proteins changed significantly during the 10-year follow-up (multiple testing-adjusted alpha = 0.00059), most showing an increase. The change in eGFR was inversely related to changes of protein levels for the vast majority of proteins (74%). The change in hemoglobin was significantly related to the change in 40% of the evaluated proteins, with no obvious preference of the direction of these relationships.CONCLUSION: The majority of evaluated proteins increased with aging in adults. Therefore, normal ranges for proteins might be given in age-strata. The increase in protein levels was associated with the degree of reduction in eGFR for the majority of proteins, while no clear pattern was seen for the relationships between the proteins and the change in hemoglobin levels. Studies on changes in urinary proteins are warranted to understand the association between the reduction in eGFR and increase in plasma protein levels.
13.	Magnusson, Patrik K. E., et al. (författare) The Swedish Twin Registry : establishment of a biobank and other recent developments 2013 Ingår i: Twin Research and Human Genetics. - Cambridge, United Kingdom : Cambridge University Press. - 1832-4274 .- 1839-2628. ; 16:1, s. 317-329 Tidskriftsartikel (refereegranskat)abstract The Swedish Twin Registry (STR) today contains more than 194,000 twins and more than 75,000 pairs have zygosity determined by an intra-pair similarity algorithm, DNA, or by being of opposite sex. Of these, approximately 20,000, 25,000, and 30,000 pairs are monozygotic, same-sex dizygotic, and opposite-sex dizygotic pairs, respectively. Since its establishment in the late 1950s, the STR has been an important epidemiological resource for the study of genetic and environmental influences on a multitude of traits, behaviors, and diseases. Following large investments in the collection of biological specimens in the past 10 years we have now established a Swedish twin biobank with DNA from 45,000 twins and blood serum from 15,000 twins, which effectively has also transformed the registry into a powerful resource for molecular studies. We here describe the main projects within which the new collections of both biological samples as well as phenotypic measures have been collected. Coverage by year of birth, zygosity determination, ethnic heterogeneity, and influences of in vitro fertilization are also described.
14.	Mendoza, Patricia, et al. (författare) DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as an Alk target in the Drosophila visceral mesoderm 2021 Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 148:23 Tidskriftsartikel (refereegranskat)abstract Development of the Drosophila visceral muscle depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signaling, which specifies founder cells (FCs) in the circular visceral mesoderm (VM). Although Alk activation by its ligand Jelly Belly (Jeb) is well characterized, few target molecules have been identified. Here, we used targeted DamID (TaDa) to identify Alk targets in embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differentially expressed genes, including the Snail/Scratch family transcription factor Kahuli (Kah). We confirmed Kah mRNA and protein expression in the VM, and identified midgut constriction defects in Kah mutants similar to those of pointed (pnt). ChIP and RNA-Seq data analysis defined a Kah target-binding site similar to that of Snail, and identified a set of common target genes putatively regulated by Kah and Pnt during midgut constriction. Taken together, we report a rich dataset of Alk-responsive loci in the embryonic VM and functionally characterize the role of Kah in the regulation of embryonic midgut morphogenesis.
15.	Nelander, Sven, 1974, et al. (författare) Predictive screening for regulators of conserved functional gene modules (gene batteries) in mammals 2005 Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 6:1 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The expression of gene batteries, genomic units of functionally linked genes which are activated by similar sets of cis- and trans-acting regulators, has been proposed as a major determinant of cell specialization in metazoans. We developed a predictive procedure to screen the mouse and human genomes and transcriptomes for cases of gene-battery-like regulation. RESULTS: In a screen that covered approximately 40 percent of all annotated protein-coding genes, we identified 21 co-expressed gene clusters with statistically supported sharing of cis-regulatory sequence elements. 66 predicted cases of over-represented transcription factor binding motifs were validated against the literature and fell into three categories: (i) previously described cases of gene battery-like regulation, (ii) previously unreported cases of gene battery-like regulation with some support in a limited number of genes, and (iii) predicted cases that currently lack experimental support. The novel predictions include for example Sox 17 and RFX transcription factor binding sites that were detected in approximately 10% of all testis specific genes, and HNF-1 and 4 binding sites that were detected in approximately 30% of all kidney specific genes respectively. The results are publicly available at http://www.wlab.gu.se/lindahl/genebatteries. CONCLUSION: 21 co-expressed gene clusters were enriched for a total of 66 shared cis-regulatory sequence elements. A majority of these predictions represent novel cases of potential co-regulation of functionally coupled proteins. Critical technical parameters were evaluated, and the results and the methods provide a valuable resource for future experimental design.
16.	Nicholls, Thomas J., et al. (författare) Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA 2018 Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 69:1 Tidskriftsartikel (refereegranskat)abstract How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network. The importance of this process is highlighted in a patient with mitochondrial disease caused by biallelic pathogenic variants in TOP3A, characterized by muscle-restricted mtDNA deletions and chronic progressive external ophthalmoplegia (CPEO) plus syndrome. Our work establishes Top3α as an essential component of the mtDNA replication machinery and as the first component of the mtDNA separation machinery. Nicholls et al. identify a role for topoisomerase 3α in the separation of mtDNA following replication. Loss of Top3α activity impairs mtDNA segregation and, consequently, segregation of the mtDNA nucleoid within the mitochondrial network. Mutations in TOP3A cause human mitochondrial disease associated with mtDNA deletions and impaired mtDNA separation. © 2017 Elsevier Inc.
17.	Nilsson, Erik, 1975-, et al. (författare) Pregnancy Associated Plasma Protein-A as a Cardiovascular Risk Marker in Patients with Stable Coronary Heart Disease During 10 Years Follow-Up-A CLARICOR Trial Sub-Study 2020 Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 9:1 Tidskriftsartikel (refereegranskat)abstract Elevated pregnancy-associated plasma protein A (PAPP-A) is associated with mortality in acute coronary syndromes. Few studies have assessed PAPP-A in stable coronary artery disease (CAD) and results are conflicting. We assessed the 10-year prognostic relevance of PAPP-A levels in stable CAD. The CLARICOR trial was a randomized controlled clinical trial including outpatients with stable CAD, randomized to clarithromycin versus placebo. The placebo group constituted our discovery cohort (n = 1.996) and the clarithromycin group the replication cohort (n = 1.975). The composite primary outcome was first occurrence of cardiovascular event or death. In the discovery cohort, incidence rates (IR) for the composite outcome were higher in those with elevated PAPP-A (IR 12.72, 95% Confidence Interval (CI) 11.0-14.7 events/100 years) compared to lower PAPP-A (IR 8.78, 8.25-9.34), with comparable results in the replication cohort. Elevated PAPP-A was associated with increased risk of the composite outcome in both cohorts (discovery Hazard Ratio (HR) 1.45, 95% CI 1.24-1.70; replication HR 1.29, 95% CI 1.10-1.52). In models adjusted for established risk factors, these trends were attenuated. Elevated PAPP-A was associated with higher all-cause mortality in both cohorts. We conclude that elevated PAPP-A levels are associated with increased long-term mortality in stable CAD, but do not improve long-term prediction of death or cardiovascular events when added to established predictors.
18.	Pandey, Gaurav Kumar, et al. (författare) The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. 2014 Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 26:5, s. 722-737 Tidskriftsartikel (refereegranskat)abstract Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.
19.	Sayin, Volkan I., 1983, et al. (författare) Zfp148 Deficiency Causes Lung Maturation Defects and Lethality in Newborn Mice That Are Rescued by Deletion of p53 or Antioxidant Treatment 2013 Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2 Tidskriftsartikel (refereegranskat)abstract The transcription factor Zfp148 (Zbp-89, BFCOL, BERF1, htβ) interacts physically with the tumor suppressor p53 and is implicated in cell cycle control, but the physiological role of Zfp148 remains unknown. Here we show that Zfp148 deficiency leads to respiratory distress and lethality in newborn mice. Zfp148 deficiency prevented structural maturation of the prenatal lung without affecting type II cell differentiation or surfactant production. BrdU analyses revealed that Zfp148 deficiency caused proliferation arrest of pulmonary cells at E18.5–19.5. Similarly, Zfp148-deficient fibroblasts exhibited proliferative arrest that was dependent on p53, raising the possibility that cell stress is part of the underlying mechanism. Indeed, Zfp148 deficiency lowered the threshold for activation of p53 under oxidative conditions. Moreover, both in vivo and cellular phenotypes were rescued on Trp53+/− or Trp53−/− backgrounds and by antioxidant treatment. Thus, Zfp148 prevents respiratory distress and lethality in newborn mice by attenuating oxidative stress–dependent p53-activity during the saccular stage of lung development. Our results establish Zfp148 as a novel player in mammalian lung maturation and demonstrate that Zfp148 is critical for cell cycle progression in vivo.
20.	Stenberg, Erik, 1979-, et al. (författare) Association between attention deficit hyperactivity disorder and outcomes after metabolic and bariatric surgery : a nationwide propensity-matched cohort study 2023 Ingår i: Surgery for Obesity and Related Diseases. - : Elsevier. - 1550-7289 .- 1878-7533. ; 19:2, s. 92-100 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The risks and benefits of metabolic and bariatric surgery for patients with attention deficit hyperactivity disorder (ADHD) remain to be investigated.OBJECTIVE: The aim of this study was to assess short- and long-term outcomes after metabolic and bariatric surgery in patients with previous ADHD compared with matched control individuals.SETTING: Registry based.METHODS: This 2-staged matched-cohort study included all adults with a body mass index of ≥30 kg/m2 who underwent primary Roux-en-Y gastric bypass or sleeve gastrectomy from 2007 until 2017 registered in the Scandinavian Obesity Surgery Registry. Patients with prescribed medication for ADHD were matched with control individuals without ADHD with a follow-up of up to 11 years after surgery.RESULTS: Among 1431 patients with ADHD and 2862 control individuals (mean body mass index, 42 kg/m2; mean age, 35 years), no difference in weight loss or follow-up attendance over 2 years was seen. ADHD was associated with a higher risk for early postoperative complications (odds ratio [OR] = 1.31; 95% confidence interval [CI], 1.05-1.63), self-harm (hazards ratio [HR] = 1.39; 95% CI, 1.11-1.75), and substance abuse (HR = 1.34; 95% CI, 1.16-1.55), while associations with overall mortality (HR = 1.42; 95% CI, .99-2.03), major adverse cardiovascular and cerebrovascular events (HR = 1.93; 95% CI, .98-3.83), and effects on obesity-related diseases were uncertain. ADHD was associated with a lower health-related quality of life in all aspects before surgery. These differences increased for mental and obesity-related aspects but remained unchanged over time for physical aspects.CONCLUSIONS: Compared with patients without ADHD, patients treated pharmacologically for ADHD experience similar weight loss and remission of obesity-related diseases without an increased risk for serious complications but report a lower health-related quality of life and have an increased risk of substance abuse and self-harm. This further emphasizes the need for close follow-up care for this group of individuals.
21.	Akrami, Rozita, et al. (författare) Comprehensive Analysis of Long Non-Coding RNAs in Ovarian Cancer Reveals Global Patterns and Targeted DNA Amplification. 2013 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11 Tidskriftsartikel (refereegranskat)abstract Long non-coding RNAs (lncRNAs) are emerging as potent regulators of cell physiology, and recent studies highlight their role in tumor development. However, while established protein-coding oncogenes and tumor suppressors often display striking patterns of focal DNA copy-number alteration in tumors, similar evidence is largely lacking for lncRNAs. Here, we report on a genomic analysis of GENCODE lncRNAs in high-grade serous ovarian adenocarcinoma, based on The Cancer Genome Atlas (TCGA) molecular profiles. Using genomic copy-number data and deep coverage transcriptome sequencing, we derived dual copy-number and expression data for 10,419 lncRNAs across 407 primary tumors. We describe global correlations between lncRNA copy-number and expression, and associate established expression subtypes with distinct lncRNA signatures. By examining regions of focal copy-number change that lack protein-coding targets, we identified an intergenic lncRNA on chromosome 1, OVAL, that shows narrow focal genomic amplification in a subset of tumors. While weakly expressed in most tumors, focal amplification coincided with strong OVAL transcriptional activation. Screening of 16 other cancer types revealed similar patterns in serous endometrial carcinomas. This shows that intergenic lncRNAs can be specifically targeted by somatic copy-number amplification, suggestive of functional involvement in tumor initiation or progression. Our analysis provides testable hypotheses and paves the way for further study of lncRNAs based on TCGA and other large-scale cancer genomics datasets.
22.	Alaei-Mahabadi, Babak, et al. (författare) Global analysis of somatic structural genomic alterations and their impact on gene expression in diverse human cancers. 2016 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 113:48, s. 13768-13773 Tidskriftsartikel (refereegranskat)abstract Tumor genomes are mosaics of somatic structural variants (SVs) that may contribute to the activation of oncogenes or inactivation of tumor suppressors, for example, by altering gene copy number amplitude. However, there are multiple other ways in which SVs can modulate transcription, but the general impact of such events on tumor transcriptional output has not been systematically determined. Here we use whole-genome sequencing data to map SVs across 600 tumors and 18 cancers, and investigate the relationship between SVs, copy number alterations (CNAs), and mRNA expression. We find that 34% of CNA breakpoints can be clarified structurally and that most amplifications are due to tandem duplications. We observe frequent swapping of strong and weak promoters in the context of gene fusions, and find that this has a measurable global impact on mRNA levels. Interestingly, several long noncoding RNAs were strongly activated by this mechanism. Additionally, SVs were confirmed in telomere reverse transcriptase (TERT) upstream regions in several cancers, associated with elevated TERT mRNA levels. We also highlight high-confidence gene fusions supported by both genomic and transcriptomic evidence, including a previously undescribed paired box 8 (PAX8)-nuclear factor, erythroid 2 like 2 (NFE2L2) fusion in thyroid carcinoma. In summary, we combine SV, CNA, and expression data to provide insights into the structural basis of CNAs as well as the impact of SVs on gene expression in tumors.
23.	Alaei-Mahabadi, Babak, et al. (författare) Limited evidence for evolutionarily conserved targeting of long non-coding RNAs by microRNAs. 2013 Ingår i: Silence. - 1758-907X. ; 4:1 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as important regulators of cell physiology, but it is yet unknown to what extent lncRNAs have evolved to be targeted by microRNAs. Comparative genomics has previously revealed widespread evolutionarily conserved microRNA targeting of protein-coding mRNAs, and here we applied a similar approach to lncRNAs. FINDINGS: We used a map of putative microRNA target sites in lncRNAs where site conservation was evaluated based on 46 vertebrate species. We compared observed target site frequencies to those obtained with a random model, at variable prediction stringencies. While conserved sites were not present above random expectation in intergenic lncRNAs overall, we observed a marginal over-representation of highly conserved 8-mer sites in a small subset of cytoplasmic lncRNAs (12 sites in 8 lncRNAs at 56% false discovery rate, P = 0.10). CONCLUSIONS: Evolutionary conservation in lncRNAs is generally low but patch-wise high, and these patches could, in principle, harbor conserved target sites. However, while our analysis efficiently detected conserved targeting of mRNAs, it provided only limited and marginally significant support for conserved microRNA-lncRNA interactions. We conclude that conserved microRNA-lncRNA interactions could not be reliably detected with our methodology.
24.	Alaei-Mahabadi, Babak, et al. (författare) Systematic investigation of promoter substitutions resulting from somatic intrachromosomal structural alterations in diverse human cancers 2020 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1 Tidskriftsartikel (refereegranskat)abstract One of the ways in which genes can become activated in tumors is by somatic structural genomic rearrangements leading to promoter swapping events, typically in the context of gene fusions that cause a weak promoter to be substituted for a strong promoter. While identifiable by whole genome sequencing, limited availability of this type of data has prohibited comprehensive study of the phenomenon. Here, we leveraged the fact that copy number alterations (CNAs) arise as a result of structural alterations in DNA, and that they may therefore be informative of gene rearrangements, to pinpoint recurrent promoter swapping at a previously intractable scale. CNA data from nearly 9500 human tumors was combined with transcriptomic sequencing data to identify several cases of recurrent activating intrachromosomal promoter substitution events, either involving proper gene fusions or juxtaposition of strong promoters to gene upstream regions. Our computational screen demonstrates that a combination of CNA and expression data can be useful for identifying novel fusion events with potential driver roles in large cancer cohorts.
25.	Allentoft, Morten E., et al. (författare) Population genomics of post-glacial western Eurasia 2024 Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311 Tidskriftsartikel (refereegranskat)abstract Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
26.	Andersén, Åsa, 1975-, et al. (författare) Strengthened General Self-Efficacy with Multidisciplinary Vocational Rehabilitation in Women on Long-Term Sick Leave : A Randomised Controlled Trial 2018 Ingår i: Journal of occupational rehabilitation. - : Springer Science and Business Media LLC. - 1053-0487 .- 1573-3688. ; 28:4, s. 691-700 Tidskriftsartikel (refereegranskat)abstract Purpose To investigate the effects of two vocational rehabilitation interventions on self-efficacy, for women on long-term sick leave ≥ 1 year due to chronic pain and/or mental illness. Methods This study uses data from a randomised controlled trial consisting of two phases and comprising 401 women on long-term sick leave. They were allocated to either (1) a multidisciplinary team assessment and multimodal intervention (TEAM), (2) acceptance and commitment therapy (ACT), or (3) control group. Data were collected through repeated measurements from self-reported questionnaires before intervention, 6 and 12 months later and registry data. Data from measurements of general self-efficacy, sociodemographics, anxiety and depression were analysed with linear regression analyses. Results During the intervention period, the women in the TEAM group’s self-efficacy mean increased from 2.29 to 2.74. The adjusted linear regression model, which included group allocation, sociodemographics, self-efficacy pre-treatment, anxiety and depression showed increased self-efficacy for those in the TEAM intervention at 12 months (B = 0.25, 95% CI 0.10–0.41). ACT intervention had no effect on self-efficacy at 12 months (B = 0.02, 95% CI − 0.16 to 0.19). The results in the adjusted model also showed that higher self-efficacy at pre-treatment was associated with a higher level of self-efficacy at 12 months (B = 0.68, 95% CI 0.54–0.81). Conclusion A multidisciplinary team assessment and multimodal intervention increased self-efficacy in women on sick leave for an extremely long time (mean 7.8 years) who had a low mean level of self-efficacy prior to inclusion. Thus, self-efficacy needs to be addressed in vocational rehabilitation.
27.	André, Erik, 1975, et al. (författare) Acceptance of Low-Carbon School Meals with and without Information—A Controlled Intervention Study 2024 Ingår i: Journal of Consumer Policy. - 0168-7034 .- 1573-0700. ; 47:1, s. 109-125 Tidskriftsartikel (refereegranskat)abstract This controlled intervention study focused on optimizing a school lunch menu to achieve a 20% reduction in greenhouse gas emissions. The objective was to evaluate the impact of introducing a low-carbon menu on pupils’ acceptance of school meals, as well as to assess whether providing information about the menu change independently influenced pupils’ acceptance. The study was conducted across six compulsory schools in a Swedish municipality, divided into three groups: schools implementing a menu change only (Menu), schools implementing a menu change with clear information provided to pupils (Menu + Info), and control schools serving the standard menu (Control). During a seven-week baseline period, all schools served the standard menu. Subsequently, for seven weeks, Menu and Menu + Info schools transitioned to a low-carbon menu achieved through the utilization of low-carbon recipes—reducing the proportion of food items with significant climate footprints while maintaining the recommended nutritional standards. In Menu + Info schools, pupils were presented with an informative video about the menu change during class. The acceptance of the low-carbon menu was evaluated through daily measurements of food consumption, plate waste, and meal satisfaction surveys. The study’s findings revealed that neither the menu change nor the information significantly affected the pupils’ acceptance of the new menu. These results align with prior studies, reinforcing the viability of employing low-carbon recipes to reduce the climate footprint of school meals. Moreover, this study demonstrates that providing supplemental information for transparency or educational purposes can be implemented without adversely affecting menu acceptance.
28.	André, Erik, 1975, et al. (författare) Om politikerna vågar kan de hjälpa oss att äta rätt 2020 Ingår i: Dagens Nyheter (DN). - 1101-2447. Tidskriftsartikel (populärvet., debatt m.m.)
29.	Arnrup, Roland, et al. (författare) Centrala universitetsvärden hotas av bolagiseringsidén 2013 Ingår i: Dagens Nyheter. - Stockholm : AB Dagens Nyheter. - 1101-2447. ; :22 Oktober, 2013 Tidskriftsartikel (populärvet., debatt m.m.)
30.	Arvey, Aaron, et al. (författare) Target mRNA abundance dilutes microRNA and siRNA activity 2010 Ingår i: Molecular Systems Biology. - 1744-4292. ; 6:363 Tidskriftsartikel (refereegranskat)
31.	Ashouri, Arghavan, 1987, et al. (författare) Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.
32.	Asplund, Annika, 1979, et al. (författare) Hypoxic regulation of secreted proteoglycans in macrophages. 2010 Ingår i: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 20:1, s. 33-40 Tidskriftsartikel (refereegranskat)abstract Macrophages are prominent in hypoxic areas of atherosclerotic lesions, and their secreted proteoglycans (PG), such as versican, can modulate the retention of lipoproteins and the activity of enzymes, cytokines, and growth factors involved in atherogenesis. In this study, we report the effects of hypoxia on PG secreted by human monocyte-derived macrophages (HMDM) and the potential regulation by the transcription factor hypoxia-inducible factor (HIF-1alpha and HIF-2alpha). We found that versican co-localized with HIF-1alpha in macrophage-rich areas in human advanced atherosclerotic lesions. Versican and perlecan mRNA expression increased after exposure to 0.5% O(2) (hypoxia) compared with 21% O(2) (control cells). Using precursors to GAG biosynthesis combined with immunoabsorption with a versican antibody an increased versican synthesis was detected at hypoxia. Furthermore, siRNA knockdown of HIF-1alpha and HIF-2alpha in THP-1 cells showed that the hypoxic induction of versican and perlecan mRNA expression involved HIF signaling. Versican expression was co-regulated by HIF-1alpha and HIF-2alpha but expression of perlecan was influenced only by HIF-1alpha and not by HIF-2alpha knockdown. The results show that oxygen concentration is an important modulator of PG expression in macrophages. This may be a novel component of the complex role of macrophages in atherosclerosis.
33.	Bandaru, Manoj Kumar, 1987-, et al. (författare) Apoc2 mutant zebrafish: a model for hypertriglyceridemia and early-stage atherosclerosis Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Zebrafish larvae in a hypertriglyceridemic background can be useful to identify and characterize causal genes for triglyceride metabolism. A previous, small-scale study suggested that apolipoprotein C-II (apoc2)-mutant zebrafish larvae can be used to model hypertriglyceridemia-induced atherosclerosis. We aimed to replicate these findings in a large-scale study and asses if APOC-II may represent a useful therapeutic target. We generated apoc2 mutant zebrafish using CRISPR-Cas9 and examined cardiometabolomic traits in their offspring (F1 generation). Systematic characterization of 384 larvae using our image and assay-based, high-throughput pipeline showed that compound heterozygous larvae for loss of function mutations in apoc2 (n=35) have higher whole-body levels of triglycerides (0.71±0.16 SD), HDL cholesterol (0.32±0.15 SD) and total cholesterol (0.37±0.18 SD), and a trend for lower whole-body glucose levels (0.23±0.14 SD) compared with larvae without mutations in apoc2 (n=174). Such larvae also tended to have more vascular lipid deposition, however this effect did not reach significance (P=0.12). Interestingly, the trends for lower whole-body glucose levels and more vascular lipid deposition in larvae with anticipated loss of functional apoc2 reached significance when larvae (n=3812) from other screens, in which apoc2 was not experimentally perturbed were included as additional wildtype controls. Thus, our large-scale study confirms the role of apoc2 in hypertriglyceridemia and early-stage atherosclerosis. While apoc2 mutant zebrafish model can be used as a genetic background to identify and characterize causal genes for triglyceride metabolism, independent and opposite effects on triglycerides and glucose suggest that APOC-II is likely not a suitable target for prevention and treatment of coronary artery disease.
34.	Bandaru, Manoj Kumar, 1987-, et al. (författare) Image-based, in vivo characterization of cardiometabolic consequences of mutations in pcsk9 Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Based on the association of loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) with low plasma LDL cholesterol levels, inhibition of the PCSK9 protein using monoclonal antibodies have emerged as an effective treatment option to lower LDL cholesterol levels and reduce the risk of coronary artery disease. Despite these beneficial effects, PCSK9 inhibitors may increase the risk of diabetes. In this study, we mimicked the mechanistic action of PCSK9 inhibitors in humans by inducing mutations in pcsk9 in zebrafish and examining their effects on dyslipidemia, early-stage atherosclerosis and diabetes-related traits in data from nearly 5000 zebrafish larvae. At 10 days of age, larvae with mutations in pcsk9 were characterized by lower whole-body LDL cholesterol levels (beta±SE -0.056±0.025 SD units) and protection against early-stage atherosclerosis, with less vascular lipid deposition (-0.133±0.035 SD) and less co-localization of macrophages with lipids (-0.086±0.032 SD). Mutant larvae also had fewer pancreatic β-cells (-0.153±0.055 SD). Thus, our findings in pcsk9 mutant larvae are in line with results from people carrying loss-of-function PCSK9 mutations, and are also in line with the effects of PCSK9 inhibitors in humans. Further, our results suggest that mutations in pcsk9 may increase the risk of diabetes through a direct effect on pancreatic β-cells.
35.	Bandaru, Sashidar, et al. (författare) Deficiency of filamin A in endothelial cells impairs left ventricular remodeling after myocardial infarction. : Endothelial filamin A impacts cardiac remodeling. 2015 Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 105:2, s. 151-159 Tidskriftsartikel (refereegranskat)abstract Actin-binding protein filamin A (FLNA) regulates signal transduction important for cell locomotion, but the role of FLNA after myocardial infarction (MI) has not been explored. The main purpose of this study was to determine the impact of endothelial deletion of FLNA on post-MI remodeling of the left ventricle (LV).
36.	Basu, Swaraj, et al. (författare) A Catalogue of Putative cis-Regulatory Interactions Between Long Non-coding RNAs and Proximal Coding Genes Based on Correlative Analysis Across Diverse Human Tumors 2018 Ingår i: G3-Genes Genomes Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 8:6, s. 2019-2025 Tidskriftsartikel (refereegranskat)abstract Antisense transcripts and other long non-coding RNAs are pervasive in mammalian cells, and some of these molecules have been proposed to regulate proximal protein-coding genes in cis. For example, non-coding transcription can contribute to inactivation of tumor suppressor genes in cancer, and antisense transcripts have been implicated in the epigenetic inactivation of imprinted genes. However, our knowledge is still limited and more such regulatory interactions likely await discovery. Here, we make use of available gene expression data from a large compendium of human tumors to generate hypotheses regarding non-coding-to-coding cis-regulatory relationships with emphasis on negative associations, as these are less likely to arise for reasons other than cis-regulation. We document a large number of possible regulatory interactions, including 193 coding/non-coding pairs that show expression patterns compatible with negative cis-regulation. Importantly, by this approach we capture several known cases, and many of the involved coding genes have known roles in cancer. Our study provides a large catalog of putative non-coding/coding cis-regulatory pairs that may serve as a basis for further experimental validation and characterization.
37.	Boström, Martin, et al. (författare) Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer. 2022 Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1 Tidskriftsartikel (refereegranskat)abstract Cancer gene discovery is reliant on distinguishing driver mutations from a multitude of passenger mutations in tumour genomes. While driver genes may be revealed based on excess mutation recurrence or clustering, there is a need for orthogonal principles. Here, we take advantage of the fact that non-cancer genes, containing only passenger mutations under neutral selection, exhibit a likelihood of mutagenesis in a given tumour determined by the tumour's mutational signature and burden. This relationship can be disrupted by positive selection, leading to a difference in the distribution of mutated cases across a cohort for driver and passenger genes. We apply this principle to detect cancer drivers independently of recurrence in large pan-cancer cohorts, and show that our method (SEISMIC) performs comparably to traditional approaches and can provide resistance to known confounding mutational phenomena. Being based on a different principle, the approach provides a much-needed complement to existing methods for detecting signals of selection.
38.	Boström, Pontus, 1982, et al. (författare) The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes. 2010 Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:8, s. 1870-8 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS: We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS: We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS: We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
39.	Brikell, Isabell, et al. (författare) COMMON GENETIC RISK VARIANTS FOR ADHD CONTRIBUTE TO CHILDHOOD NEURODEVELOPMENTAL AND EXTERNALIZING TRAITS IN THE POPULATION 2019 Ingår i: European Neuropsychopharmacology. - : Elsevier. - 0924-977X .- 1873-7862. ; 29:Suppl. 3, s. S811-S811 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
40.	Brikell, Isabell, et al. (författare) The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology 2020 Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:8, s. 1809-1821 Tidskriftsartikel (refereegranskat)abstract Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R 2 = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.
41.	Carlsson, Axel C, et al. (författare) Use of proteomics to investigate kidney function decline over 5 years 2017 Ingår i: American Society of Nephrology. Clinical Journal. - 1555-9041 .- 1555-905X. ; 12:8, s. 1226-1235 Tidskriftsartikel (refereegranskat)abstract BACKGROUND AND OBJECTIVES: Using a discovery/replication approach, we investigated associations between a multiplex panel of 80 circulating proteins associated with cardiovascular pathology or inflammation, and eGFR decline per year and CKD incidence.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used two cohorts, the Prospective Investigation of the Vasculature in Uppsala Seniors Study (PIVUS; n=687, mean age of 70 years, 51% women) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=360 men, mean age of 78 years), with 5-year follow-up data on eGFR. There were 231 and 206 incident cases of CKD during follow-up in the PIVUS and ULSAM studies, respectively. Proteomic profiling of 80 proteins was assessed by a multiplex assay (proximity extension assay). The assay uses two antibodies for each protein and a PCR step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations.RESULTS: In the discovery cohort from the PIVUS Study, 28 plasma proteins were significantly associated with eGFR decline per year, taking into account the multiple testing. Twenty of these proteins were significantly associated with eGFR decline per year in the replication cohort from the ULSAM Study after adjustment for age, sex, cardiovascular risk factors, medications, and urinary albumin-to-creatinine ratio (in order of significance: TNF-related apoptosis-inducing ligand receptor 2, CD40L receptor, TNF receptor 1, placenta growth factor, thrombomodulin, urokinase plasminogen activator surface receptor, growth/differentiation factor 15, macrophage colony-stimulating factor 1, fatty acid-binding protein, cathepsin D, resistin, kallikrein 11, C-C motif chemokine 3, proteinase-activated receptor 1, cathepsin L, chitinase 3-like protein 1, TNF receptor 2, fibroblast growth factor 23, monocyte chemotactic protein 1, and kallikrein 6). Moreover, 11 of the proteins predicted CKD incidence (marked with above). No protein consistently predicted eGFR decline per year independently of baseline eGFR in both cohorts.CONCLUSIONS: Several circulating proteins involved in phosphate homeostasis, inflammation, apoptosis, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction were associated with worsening kidney function. Multiplex proteomics appears to be a promising way of discovering novel aspects of kidney disease pathology.
42.	Chen, Cen, et al. (författare) Associations Between General and Specific Mental Health Conditions in Young Adulthood and Cardiometabolic Complications in Middle Adulthood : A 40-Year Longitudinal Familial Coaggregation Study of 672,823 Swedish Individuals 2024 Ingår i: American Journal of Psychiatry. - : HighWire Press. - 0002-953X .- 1535-7228. Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability to psychopathology or confounded by unmeasured familial factors. The authors investigated the association between psychiatric conditions in young adulthood and the risk of cardiometabolic complications in middle adulthood, up to 40 years later.METHODS: This cohort study (N=672,823) identified all individuals and their siblings born in Sweden between 1955 and 1962 and followed the cohort through 2013. Logistic regression models were used to estimate the bivariate associations between 10 psychiatric conditions or criminal convictions and five cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the comorbidity among psychiatric conditions and criminal convictions. The cardiometabolic complications were then regressed on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs.RESULTS: Each psychiatric condition significantly increased the risk of cardiometabolic complications. These associations appeared nonspecific, as multivariate models indicated that most were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals' general psychopathology and their siblings' cardiometabolic complications. The same pattern was evident for the specific internalizing and psychotic factors.CONCLUSIONS: Associations between mental disorders in early life and later long-term risk of cardiometabolic complications appeared to be attributable to a general liability to psychopathology. Familial coaggregation analyses suggested that the elevated risk could not be attributed to confounders shared within families. One possibility is that lifestyle-based interventions may reduce the risk of later cardiometabolic complications for patients with several mental disorders.
43.	Du Rietz, Ebba, et al. (författare) Overlap between attention-deficit hyperactivity disorder and neurodevelopmental, externalising and internalising disorders : separating unique from general psychopathology effects 2021 Ingår i: British Journal of Psychiatry. - : Royal College of Psychiatry. - 0007-1250 .- 1472-1465. ; 218:1, s. 35-42 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Although attention-deficit hyperactivity disorder (ADHD) is classified as a neurodevelopmental disorder in the latest diagnostic manuals, it shows phenotypic and genetic associations of similar magnitudes across neurodevelopmental, externalising and internalising disorders.AIMS: To investigate if ADHD is aetiologically more closely related to neurodevelopmental than externalising or internalising disorder clusters, after accounting for a general psychopathology factor.METHOD: Full and maternal half-sibling pairs (N = 774 416), born between 1980 and 1995, were identified from the Swedish Medical Birth and Multi-Generation Registers, and ICD diagnoses were obtained from the Swedish National Patient Register. A higher-order confirmatory factor analytic model was fitted to examine associations between ADHD and a general psychopathology factor, as well as a neurodevelopmental, externalising and internalising subfactor. Quantitative genetic modelling was performed to estimate the extent to which genetic, shared and non-shared environmental effects influenced the associations with ADHD.RESULTS: ADHD was significantly and strongly associated with all three factors (r = 0.67-0.75). However, after controlling for a general psychopathology factor, only the association between ADHD and the neurodevelopmental-specific factor remained moderately strong (r = 0.43, 95% CI = 0.42-0.45) and was almost entirely influenced by genetic effects. In contrast, the association between ADHD and the externalising-specific factor was smaller (r = 0.25, 95% CI = 0.24-0.27), and largely influenced by non-shared environmental effects. There remained no internalising-specific factor after accounting for a general factor.CONCLUSIONS: Findings suggest that ADHD comorbidity is largely explained by genetically influenced general psychopathology, but the strong link between ADHD and other neurodevelopmental disorders is also substantially driven by unique genetic influences.
44.	Duggimpudi, Sujitha, et al. (författare) The Cell Cycle Regulator CCDC6 Is a Key Target of RNA-Binding Protein EWS. 2015 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3 Tidskriftsartikel (refereegranskat)abstract Genetic translocation of EWSR1 to ETS transcription factor coding region is considered as primary cause for Ewing sarcoma. Previous studies focused on the biology of chimeric transcription factors formed due to this translocation. However, the physiological consequences of heterozygous EWSR1 loss in these tumors have largely remained elusive. Previously, we have identified various mRNAs bound to EWS using PAR-CLIP. In this study, we demonstrate CCDC6, a known cell cycle regulator protein, as a novel target regulated by EWS. siRNA mediated down regulation of EWS caused an elevated apoptosis in cells in a CCDC6-dependant manner. This effect was rescued upon re-expression of CCDC6. This study provides evidence for a novel functional link through which wild-type EWS operates in a target-dependant manner in Ewing sarcoma.
45.	Eich, Torsten, 1972-, et al. (författare) Rapid desensitisation of anti-HLA antibodies using the IgG degrading enzyme IdeS in sensitized patients with chronic kidney disease 2016 Ingår i: Tissue Antigens. - 0001-2815 .- 1399-0039. ; 87:4, s. 226-227 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
46.	Einarsdottir, Berglind Osk, 1979, et al. (författare) A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma 2018 Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8 Tidskriftsartikel (refereegranskat)abstract Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
47.	Elliott, Kerryn, et al. (författare) Base-resolution UV footprinting by sequencing reveals distinctive damage signatures for DNA-binding proteins 2023 Ingår i: Nature Communications. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Decades ago, it was shown that proteins binding to DNA can quantitatively alter the formation of DNA damage by UV light. This established the principle of UV footprinting for non-intrusive study of protein-DNA contacts in living cells, albeit at limited scale and precision. Here, we perform deep base-resolution quantification of the principal UV damage lesion, the cyclobutane pyrimidine dimer (CPD), at select human promoter regions using targeted CPD sequencing. Several transcription factors exhibited distinctive and repeatable damage signatures indicative of site occupancy, involving strong (up to 17-fold) position-specific elevations and reductions in CPD formation frequency relative to naked DNA. Positive damage modulation at some ETS transcription factor binding sites coincided at base level with melanoma somatic mutation hotspots. Our work provides proof of concept for the study of protein-DNA interactions at individual loci using light and sequencing, and reveals widespread and potent modulation of UV damage in regulatory regions. Proteins binding to DNA can locally alter DNA damage formation by UV light. Here, Elliott et al. generate high-resolution quantitative UV damage profiles for genomic regions of interest, revealing distinctive damage signatures for specific proteins and elevated UV damage at melanoma mutation hotspots.
48.	Elliott, Kerryn, et al. (författare) Non-coding driver mutations in human cancer. 2021 Ingår i: Nature reviews. Cancer. - : Springer Science and Business Media LLC. - 1474-1768 .- 1474-175X. ; 21:8, s. 500-509 Forskningsöversikt (refereegranskat)abstract Tumour formation involves random mutagenic events and positive evolutionary selection acting on a subset of such events, referred to as driver mutations. A decade of careful surveying of tumour DNA using exome-based analyses has revealed a multitude of protein-coding somatic driver mutations, some of which are clinically actionable. Today, a transition towards whole-genome analysis is well under way, technically enabling the discovery of potential driver mutations occurring outside protein-coding sequences. Mutations are abundant in this vast non-coding space, which is more than 50 times larger than the coding exome, but reliable identification of selection signals in non-coding DNA remains a challenge. In this Review, we discuss recent findings in the field, where the emerging landscape is one in which non-coding driver mutations appear to be relatively infrequent. Nevertheless, we highlight several notable discoveries. We consider possible reasons for the relative absence of non-coding driver events, as well as the difficulties associated with detecting signals of positive selection in non-coding DNA.
49.	Farazi, Thalia A, et al. (författare) Identification of the RNA recognition element of the RBPMS family of RNA-binding proteins and their transcriptome-wide mRNA targets. 2014 Ingår i: RNA (New York, N.Y.). - : Cold Spring Harbor Laboratory. - 1469-9001 .- 1355-8382. ; 20, s. 1090-1102 Tidskriftsartikel (refereegranskat)abstract Recent studies implicated the RNA-binding protein with multiple splicing (RBPMS) family of proteins in oocyte, retinal ganglion cell, heart, and gastrointestinal smooth muscle development. These RNA-binding proteins contain a single RNA recognition motif (RRM), and their targets and molecular function have not yet been identified. We defined transcriptome-wide RNA targets using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) in HEK293 cells, revealing exonic mature and intronic pre-mRNA binding sites, in agreement with the nuclear and cytoplasmic localization of the proteins. Computational and biochemical approaches defined the RNA recognition element (RRE) as a tandem CAC trinucleotide motif separated by a variable spacer region. Similar to other mRNA-binding proteins, RBPMS family of proteins relocalized to cytoplasmic stress granules under oxidative stress conditions suggestive of a support function for mRNA localization in large and/or multinucleated cells where it is preferentially expressed.
50.	Flentie, Kelly, et al. (författare) Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis 2019 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Scionces of the United States of America. - 0027-8424 .- 1091-6490. ; 116:21, s. 10510-10517 Tidskriftsartikel (refereegranskat)abstract Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Skapa referenser, mejla, bekava och länka

Länka till träfflistan

Resultat 1-50 av 160

Avgränsa träffmängd

Typ av publikation: tidskriftsartikel (137); konferensbidrag (15); rapport (3); annan publikation (2); doktorsavhandling (2); forskningsöversikt (1); visa fler...; visa färre...

Typ av innehåll: refereegranskat (147); övrigt vetenskapligt/konstnärligt (11); populärvet., debatt m.m. (2)

Författare/redaktör: Larsson, Erik, 1975 (77); Larsson, Henrik, 197 ... (27); Lichtenstein, Paul (24); Pettersson, Erik (19); Fagerström, Martin, ... (11); Larsson, Fredrik, 19 ... (11); visa fler...; Larsson, Anders (9); D'Onofrio, Brian M. (9); Karlsson, Joakim (9); Landén, Mikael, 1966 (7); Larsson, Erik (7); Basu, Swaraj (7); Elliott, Kerryn (7); Kuja-Halkola, Ralf (7); Ståhlberg, Anders, 1 ... (6); Alaei-Mahabadi, Baba ... (6); Lind, Lars (5); Larsson, Erik G (5); Lundström, Sebastian (5); Sayin, Volkan I., 19 ... (5); Akyürek, Levent, 196 ... (5); Tufveson, Gunnar (5); Långström, Niklas (4); Larsson, Jörgen, 196 ... (4); Eriksson, Thomas, 19 ... (4); Bengtsson, Mats (4); Falkenberg, Maria, 1 ... (4); Gustavsson, Ulf, 197 ... (4); Holmén Larsson, Jess ... (4); Nilsson, Jonas A, 19 ... (4); André, Erik, 1975 (4); Ärnlöv, Johan, 1970- (3); Nelander, Sven, 1974 (3); Palmer, Ruth H., 197 ... (3); Borén, Jan, 1963 (3); Chen, Qi (3); Almqvist, Catarina (3); Röös, Elin (3); Sander, Chris (3); Tang, Ka-Wei, 1983 (3); Zhou, Xianghua, 1973 (3); Uhler, Jay (Jennifer ... (3); Anckarsäter, Henrik, ... (3); Bäckman, Lars (3); Gumpert, Clara Helln ... (3); Samuelsson, Tore, 19 ... (3); Carlsson, Axel C. (3); Ghirardi, Laura (3); Oldfors, Anders, 195 ... (3); Ashouri, Arghavan, 1 ... (3); visa färre...

Lärosäte: Göteborgs universitet (99); Karolinska Institutet (50); Örebro universitet (33); Chalmers tekniska högskola (30); Uppsala universitet (28); Lunds universitet (10); visa fler...; Linköpings universitet (8); Umeå universitet (5); Kungliga Tekniska Högskolan (5); Högskolan Dalarna (5); Högskolan i Halmstad (2); RISE (2); Stockholms universitet (1); Handelshögskolan i Stockholm (1); Mittuniversitetet (1); Södertörns högskola (1); Linnéuniversitetet (1); visa färre...

Språk: Engelska (157); Svenska (3)

Forskningsämne (UKÄ/SCB): Medicin och hälsovetenskap (113); Naturvetenskap (44); Teknik (21); Samhällsvetenskap (9); Lantbruksvetenskap (3); Humaniora (3)

År

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se

Stäng

Kopiera och spara länken för att återkomma till aktuell vy